Development of autoimmune diseases requires coordinated expression of a number of genes that are involved in the activation, migration and effector functions of inflammatory cells. These include genes that encode costimulatory molecules, cytokines, chemokines, adhesion molecules and inflammatory enzymes. Expression of these genes is regulated by several families of transcription factors that include nuclear factor (NF)-kappaB, activator protein-1 and nuclear factor-IL-6. These factors, acting either alone or in combination, orchestrate the initiation and progression of autoimmune diseases. The long-term goal of our research is to elucidate the mechanisms of transcription factor regulation of autoimmune diseases. This proposal is based on our recent discovery that NF-kappaB1-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 or TH2 type response to self-myelin antigens. The goal of this proposal is to elucidate the mechanisms of NF- kappaB1 action in animal models of multiple sclerosis. A major challenge to study the roles of transcription factors in autoimmune diseases is that they are often expressed by a variety of cell types. In the case of NF-kappaB1, it is expressed not only by cells of the immune system, but also by cells of target organs such as brain and spinal cord. The roles of NF-kappaB1 in each of these cell types must be established before a comprehensive understanding of NF-kappaB1 action in autoimmunity can be achieved. We hypothesize that NF-kappaB1 expressed by immune cells and neural cells may play different roles in EAE: NF-kappaB1 expressed by immune cells orchestrates the activation and effector function of inflammatory cells leading to tissue injury, whereas NF-kappaB1 expressed by neural cells protects them from inflammation-induced cell death, presumably by activating anti-apoptotic genes. To test these hypotheses, we will study the roles of NF-kappaB1 in 1) activation of myelin-specific T cells, 2) formation of inflammatory lesions, and 3) death of inflammatory and neural cells in EAE. The roles of NF-kappaB1 expressed by different cell types will be dissected using transgenic adoptive transfer models and bone-marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of NF-kappaB1 action in EAE but also aid in developing a general strategy to investigate the roles of transcription factors in autoimmune diseases. Novel strategies targeting NF-kappaB may then be developed to treat or prevent autoimmune diseases.